Generally, when a compound is used as an active ingredient for medicaments, the compound is required to have chemical and physical stability for preservation of stable quality and/or easy storage and management. For the reason, such a compound is preferably produced in a stable crystal form. Also, when a compound is used as an active pharmaceutical ingredient in a drug, the most stable crystal form of the compound is selected. Moreover, Guideline for Residual Solvents in ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines makes recommendations regarding which of various solvents should be avoided/limited/used and the acceptable amounts thereof. Some solvents used in producing medicaments are toxic, and therefore, in view of safety, the amount of such a solvent remaining after a production process is desirably as small as possible. Moreover, medicaments may become charged with static electricity in the production process. Charged medicaments can adhere to a production machine, a dividing and packing machine, and the like and problems of yield deterioration and unequal packing occur. To avoid such problems, medicaments having low chargeability are preferred.
Patent Literature 1 discloses that one of uracil derivatives, tipiracil hydrochloride (chemical name: 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, hereinafter sometimes referred to as “TPI” (5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione is sometimes referred to as “tipiracil”)) represented by the following Formula (1)
has an inhibitory action on human thymidine phosphorylase and an enhancing action on the antitumor effect of trifluridine (hereinafter sometimes referred to as “FTD”). An antitumor agent “TAS-102” composed of a mixture of FTD and TPI with a molar ratio of 1 to 0.5, which is currently still under development as an oral preparation, has already been approved, in Japan, as a therapeutic agent for advanced or recurrent colorectal cancer (Non-patent Literature 1 and 2).
Examples of previously reported methods for producing tipiracil hydrochloride include a method in which tipiracil monohydrochloride 1/10 hydrate is obtained as follows: 5-chloro-6-chloromethyluracil, 2-iminopyrrolidine, and a solution of sodium ethoxide in N, N-dimethylformamide are stirred at room temperature for 14 hours; the crystallized material is separated by filtration and suspended in water; the suspension is neutralized with acetic acid; the insoluble matter is separated by filtration and dissolved in 1 N hydrochloric acid; activated carbon is added thereto; the mixture is filtered; the filtrate is concentrated under reduced pressure; and the residue is washed with ethanol and separated by filtration (Patent Literature 1). In another reported method, tipiracil hydrochloride is produced as follows: 2-iminopyrrolidine hydrochloride, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 5-chloro-6-(chloromethyl) pyrimidine-2,4-(1H,3H)-dione are allowed to react in methanol; the resulting precipitate is dissolved in 2 N hydrochloric acid at a temperature of 90° C. with heating; ethanol is added to the reaction liquid; and the liquid is left to stand at room temperature to give white crystals (Non-patent Literature 3). However, it has turned out later that the white crystals obtained by these methods were mixed crystals containing Crystal III described below.
At present, there is no known method by which a stable crystal form of highly-pure anhydrous tipiracil hydrochloride can be obtained with a high reproducibility.